Microcephaly is a devastating developmental defect that can be caused by inherited mutations such as those that inactivate the minor spliceosome or more recently Zika virus infections. In order to better understand the underlying molecular and cellular defects that cause microcephaly, we must first understand the molecular and cellular changes during normal development. The current proposal extends our finding that inactivation of the minor spliceosome in our U11 conditional knockout (cKO) mouse crossed with Emx1-Cre results in microcephaly observed at birth. We found that the primary cause of the microcephaly is loss of self-amplifying radial glial cells (RGCs) and delayed death of intermediate progenitor cells (IPCs) without the corresponding loss of neurons during early cortical development. Despite the complete loss of NPCs by E14, the developing mutant cortex managed to produce layer IV neurons that are normally born at/after E14. We found that this shift in neuron production is in conjunction with increased neurogenesis measured by EdU pulse/chase experiments. Based on these complex phenotypes, we have proposed three aims to test the hypothesis that minor spliceosome acts in a cell-type specific manner to inform cell cycle regulation, NPC competence, and neuron production. Experiments proposed in aim 1a are designed to elucidate the precise cell-cycle regulation of RGCs and IPCs and whether these two cell-types are undergoing self-amplifying or neurogenic cell divisions. In aim 1b, we explore how the changes in U11-null RGCs and IPCs impact neuron production. In aim 2, the objective is to understand the molecular underpinning of the cell-type specific effect of U11 loss. The one unique identifier of RGCs is that they divide rapidly compared to the IPCs, so the experiments proposed in aim 2a test the hypothesis that cell cycle speed confers susceptibility to loss of U11. Another possibility that the experiments proposed in aim 2b is that each cell-type has a unique signature of minor intron-containing genes (MIGs) that might make cells resistant/susceptible to U1 loss. Finally, RNAseq data showed activation of P53- medated apoptosis pathway and cell cycle defect in the U11-null tissue. The experiments proposed in aim 3a test whether rescuing cell cycle defect would prevent P53-mediated apoptosis or is P53-mediated apoptosis independent of the cell cycle defect. Aim 3b tests the idea that if P53 is ablation, would it rescue cell cycle or cell death and in turn rescue microcephaly. In all, we will find the role of this novel form of gene regulation in cortical development and in turn provide insights into microcephaly observed in diseases such as microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) and Roifman syndrome that are both caused by defective minor spliceosome.